ABSTRACT A common problem with any chronic drug therapy is non-adherence. Non-adherence to therapy, including HIV anti-retroviral therapy, can be due to a combination of factors including pill fatigue, intolerable side-affects, and the complexity of therapeutic regimens. Non-adherence is associated with a rebound in viral loads which can be accompanied by the emergence of drug-resistant HIV strains. This poses a major public health threat not only because of ensuing disease progression, but also because drug-resistant strains are spread in the population through de novo infections. Even as the HIV drug pipeline continues to generate novel and potent anti-retroviral compounds, much attention is now being directed towards developing long-lasting drug delivery options. In order for combination therapy with HAART to continue to be effective in improving AIDS-related morbidity and mortality, therapies need to be formulated so as to require infrequent and convenient dosing while achieving sustained and effective tissue concentrations. To date, the most successful strategy for prolonged and controlled delivery of small molecule treatments relies on slow-releasing nano-suspensions or polymeric microspheres that are injected either subcutaneously or intramuscularly. There are, however, many drawbacks to the injectable approach. Injectables are limited to highly potent, very hydrophobic molecules, and can produce long, sub-therapeutic tails with uncertain risk. Long-acting oral therapies are potentially the most convenient route for patients, and may offer significant advantages over injectable solutions. But no existing oral delivery system can provide more than 12-24 hours of sustained release of small molecule therapies. Lyndra has developed an orally-available, gastric-resident dosage form engineered to deliver therapeutic doses of drug(s) over a period of a week, before disintegrating and safely passing out of the body. The basic modules of the device are an elastomeric center fused to six arms made of a polymer-drug blend; break points called linkers are strategically placed in the arms to ensure timed disintegration of the dosage form, leading to quick and safe passage out of the body. We have demonstrated in large animal models that this platform is capable of once weekly administration with near steady-state pharmacokinetics for a variety of small molecule therapies. The objective of this proposal is to integrate a highly potent anti-HIV molecule into this platform for a once weekly oral regimen. In Aim 1, we will optimize a formulation of Dolutegravir, a potent integrase inhibitor, for sustained delivery from a polymeric matrix blended with various excipients that control the rate of release. In Aim 2, we will develop novel, enteric linkers that quickly dissolve in the intestinal environment. A tracer system to monitor residence of drug-loaded doses will be based on release of sub-therapeutic doses of short half-life FDA-approved drugs. Finally, in Aim 3, we propose to test gastric residence as well as pharmacokinetics of drug and tracer release in a large animal model. Our target product is a 0-size capsule comprising a single dosage form loaded with enough Dolutegravir to sustain serum levels similar to those achieved by the current clinical regimen, for one week. In the long term, we plan to develop formulations that carry combinations of highly potent anti-retrovirals and tracers that allow patients to self-track the presence of the doses.